Malformations of the human cerebral cortex represent clinically important birth defects, resulting in mental retardation, epilepsy, and cerebral palsy. Cortical malformations can range anywhere from grossly visible derangements of the cerebral hemispheres, to subtle, focal defects of cortical architecture. Consequently, the wide range of phenotypes includes profoundly crippled children as well as adults with normal intelligence who present with mild epilepsy or no symptoms at all. It is increasingly clear that many malformations of the human cortex result from the action of defective genes. We propose to map and clone genes for several autosomal recessive disorders of human cerebral cortical development that are associated with abnormal neuronal migration. Although recessively inherited human cortical malformations are clinically and genetically heterogenous, our preliminary data suggest that they can be subdivided into less heterogenous categories by careful pedigree ascertainment. Through collaborations with clinicians, pedigrees with recessive cortical malformations will be ascertained and studied by performing medical review and MRI brain imaging. Attention will particularly focus on pedigrees that show consanguinity for mapping rare recessive disease genes. For well-characterized pedigrees that show evidence for simply inherited, highly penetrant recessive traits, DNA samples will be collected and subjected to genome wide screens to find areas of genetic linkage. Linkage will be tested with standard statistical methods, and multiple distinct pedigrees with the same disorder from genetically isolated populations will be analyzed because of the likelihood of founder mutations that allow genetic fine mapping and eventual gene identification. Identifying the genes that cause recessive neuronal migration disorders of the cerebral cortex would be important for understanding normal human brain development and evolution, as well as epilepsy pathogenesis.